Lipid peroxidation has been suggested as being involved in several forms of ischemic cellular damage, both structural and functional. Membrane lipids, as well as circulating free fatty acids, are potential substrates for peroxidation. Once initiated by free radicals, lipid peroxidation is a self-propagating reaction and is thought to contribute to the irreversible cellular damage seen during periods of ischemic insult. However, no studies have definitively explored the enhanced cellular lipid peroxidation associated with ischemia and subsequent metabolic and functional defects. Therefore, I propose to study lipid peroxidation and its relationship to measurable metabolic alterations in two canine models of myocardial ischemia. In both models a region of the left ventricle will be subjected to a reduced blood flow followed by arterial and venous sampling across the ischemic region, and tissue sampling during the experimental period. These experiments are designed to study lipid peroxidation and metabolic alterations at a time prior to, and during, irreversible cellular damage. Lipid peroxidation and subsequent cellular injury will be assessed by both direct and indirect means. Formation of lipid peroxides by circulating free fatty acids, in membranes of red blood cells, and in cardiac cellular components (sarcolemma, sarcoplasmic reticulum, and mitochondria) will be measured by the iodometric reaction and the malonyldialdehyde reaction. The production/uptake of substrates of metabolism, i.e., lactate, pyruvate, and fatty acids, will be determined across the ischemic region by calculation of their arteriovenous differences. The energy balance of the ischemic and non-ischemic areas will be assessed by measurement of creatine phosphate and the adenine nucleotides (ATP, ADP, and AMP). Experimental protocols are designed to evaluate the effects of inhibition of lipid peroxidation using selective free radical scavengers for removal of initiating free radicals and lipid peroxide intermediates and inhibition of lipolysis by antilipolytic agents to prevent ischemic-induced increases in circulating free fatty acids. These studies should help define the extent of lipid peroxidation in myocardial ischemia and its relationship to the metabolic changes preceding irreversible structural damage.